Annals of Oncology 13: 10071015, 2002

Review DOI: 10.1093/annonc/mdf179

2002 European Society for Medical Oncology
Nasopharyngeal carcinoma
A. T. C. Chan*, P. M. L. Teo & P. J. Johnson
*Correspondence to: Dr A. T. C. Chan, Department of Clinical
Oncology, Prince of Wales Hospital, Chinese University of Hong Kong,
Shatin, N.T. Hong Kong, Peoples Rebublic of China.
Tel: +852-2632-2166; Fax: +852-2648-7097;
E-mail: anthonytcchan@cuhk.edu.hk
Prince of Wales Hospital, Sir Y. K. Pao Cancer Center, Chinese University of Hong Kong, Peoples Republic of China
Received 20 December 2001; revised and accepted 8 February 2002
Nasopharyngeal carcinoma (NPC) is endemic in southern China where genetic abnormalities and
EpsteinBarr virus (EBV) infection are critical in the pathogenesis of the disease. Circulating
EBV-DNA has been shown to improve prognostication and monitoring of NPC patients. Radiotherapy
is the mainstay treatment for early disease and concurrent cisplatin/radiotherapy has been demonstrated
to prolong survival in locoregionally advanced disease. Ongoing studies of targeting agents and
immunotherapeutic approaches may further improve treatment results.
Key words: EpsteinBarr virus, nasopharyngeal carcinoma, review, treatment
Introduction
Nasopharyngeal carcinoma (NPC) occurs sporadically in the
west but is endemic in southern China where it is the third
most common form of malignancy amongst men, with inci-
dence rates of between 15 and 50 per 100000 [1]. There is an
intermediate incidence in Alaskan Eskimos and in the Medi-
terranean basin.
The geographical pattern of incidence suggests a unique
interaction of environmental and genetic factors. A stepwise
progression of histological features that reflect underlying
genetic events has recently been described. Patches of dys-
plasia are the earliest recognizable lesions, presumably in
response to some environmental carcinogen. These are associ-
ated with allelic losses on the short arms of chromosomes 3
and 9 that result in inactivation of several tumor suppressor
genes, particularly p14, p15 and p16 [25]. The relevant
carcinogens have not been established but a link between the
consumption of Chinese salted fish and other salted food items
with the development of NPC has been suggested [1]. These
dysplastic areas are the origin of the tumor but are probably
insufficient in themselves to lead to further progression. At
this stage latent EpsteinBarr virus (EBV) infection becomes
critical and leads to the development of severe dysplasia.
Gains of genes on chromosome 12 and allelic loss on 11q, 13q
and 16q lead on to invasive carcinoma; metastasis is asso-
ciated with mutation of p53 and aberrant expression of
cadherins (Figure 1) [6, 7].
Nasopharyngeal carcinomas are epithelial neoplasms.
Three histopathological types are recognized in the World
Health Organization (WHO) classifications [8]. Type I is
squamous cell carcinoma (SCC) with varying degrees of
differentiation. Type II is non-keratinizing carcinoma and
type III is undifferentiated carcinoma. WHO types II and III
can be considered together as undifferentiated carcinoma of
the nasopharyngeal type (UCNT). The histological types may
be of prognostic significance with UCNT having a higher
local control rate after treatment with radiotherapy than
keratinizing SCC and UCNT has also been shown to fail more
distantly than locally [10, 11].
Presentation, imaging and staging
The most common presenting symptom is cervical lymph-
adenopathy, followed by nasal, aural and neurological symp-
toms. Only 5% of patients present with distant metastases in
series from Southern China [12, 13]. Once the diagnosis is
suspected on clinical grounds, histological confirmation of the
diagnosis is mandatory. The technique of biopsy under local
anesthesia has been found to have a diagnostic sensitivity
comparable to that obtained by examination under general
anesthesia. The biopsy is facilitated by direct visualization of
the nasopharynx with a fiberoptic nasopharyngoscope. How-
ever, since the biopsy may cause soft tissue swelling and/or a
hematoma, computed tomography (CT) scan and magnetic
resonance imaging (MRI) of the nasopharynx and the skull
base should be undertaken before the biopsy.
The primary tumor extent should be evaluated by both CT
scan and MRI. The latter is more sensitive than CT scan for the
detection of the primary tumor, its direct soft tissue extent,
regional nodal metastasis and perineural extension. Blood
vessels are clearly shown by MRI even without the use of
intravenous contrast. On the other hand, although MRI can
also demonstrate erosion into the base of the skull by virtue
of the change in signal of fatty bone marrow, CT scan is
1008
generally considered a better tool for defining bone erosion.
The role of positron emission tomography (PET) scanning in
NPC remains to be defined, although preliminary reports indi-
cate that it can be useful in detecting both local failures after
treatment and distant metastases.
Prior to 1997, several different stage classifications were
used but that described by Ho [1] was found to be superior to
the others in its ability to predict prognosis and treatment out-
come [12]. However, Hos classification was not ideal as an
international system because it comprised five overall stages
(instead of the usual practice of four), there were only three
T-stages and it did not take into account CT scan evidence of
tumor infiltration of the parapharyngeal region, a factor of
considerable prognostic significance [13].
In 1997, therefore, a new UICC/AJCC stage classification
was formulated, which incorporated all the major prognostic-
ally significant tumor parameters (Table 1). It is noteworthy
that tumors infiltrating the parapharyngeal region were asso-
ciated with a higher rate of both local failure and distant
metastasis; such cases were classified as T2b (Table 1). The
presence of orbital, infratemporal fossal and hypopharyngeal
disease was grouped together with the presence of cranial
nerve(s) palsy and intracranial tumor extension as T4. The
poor prognosis of supraclavicular nodal metastases was
recognized and classified as N3, together with very large
nodes (>6 cm) (Table 1).
Prognosis and molecular markers
NPC is one of the very few common cancers in which cure can
be anticipated even in patients with advanced disease. The
prognosis is related to the disease extent as measured by the
UICC staging system, the type of histology and, as emphas-
ized by OSullivan et al. [14], the extent to which patients
have access to an experienced treatment team with access to
modern oncological therapeutics. It seems likely that in the
near future that the level of EBV-DNA, which appears to be
prognostic independent of any of the above-mentioned
factors, will become routine and permit even more accurate
prognostication.
The demonstration that tumor-derived DNA is detectable in
the plasma and serum of cancer patients raised the possibility
that non-invasive detection and monitoring of NPC may be
feasible. Using real-time quantitative PCR, cell-free EBV-
DNA was found in the plasma of 96% of NPC patients and 7%
of controls. Advanced-stage NPC patients had higher plasma
EBV-DNA levels than tumors with early-stage disease [15].
Further studies have demonstrated that EBV-DNA may be a
valuable tool for monitoring NPC patient response during
radiotherapy and chemotherapy [16], as well as early detec-
tion of tumor recurrence [17]. In a cohort of 139 patients NPC
patients treated with a uniform radiotherapy technique and
followed up for a median period of 5.55 years, serum circulat-
ing EBV-DNA was found to be a significant prognosticator
associated with NPC-related death in a Coxs regression
analysis with a relative risk of 1.6 for each 10-fold increase in
serumEBV-DNA concentration [18]. Thus the quantitation of
EBV-DNA appears to allow improved prognostication of
NPC. The sensitivity and specificity also suggests the poten-
tial use as a screening test in areas where NPC is endemic.
Radiotherapy
Up to the early 1990s, radical radiotherapy for NPC was
delivered by two-dimensional (2D) techniques such as the one
Figure 1. Proposed tumorigenesis model for nasopharyngeal carcinoma (K.W. Lo and D. P. Huang, personal communication).
1009
described by Ho [1]. The conventional practice had been to
deliver tumoricidal radiation doses (total 6070 Gy; 22.5 Gy
per fraction in a 67 week course) to anatomical structures at
risk of tumor invasion in the vicinity of the nasopharynx by
two lateral opposing fields or multiple fields. Appropriate
shieldings were positioned at predetermined distances from
bony landmarks [1] to protect vital neural organs. The neck
was separately irradiated by another portal with avoidance of
midline structures such as the spinal cord and the larynx [1].
With two-dimensional planning techniques, the local control
rates for NPC were in the order of 80%, taking all T-stages
together [13, 19]. In our experience, the overall survival (OS)
figures after radiotherapy, using Hos technique, were 85%
for Hos stages I and II and 55% for Hos stages III and IV
(Figure 2) [13].
With advances in technology, the modern radiotherapy for
NPC should be that of three-dimensional conformal (3DCRT)
or intensity-modulated (IMRT) with inverse radiotherapy
planning. Researchers at the University of Californian at San
Francisco, Stanford University, University of Texas M.D.
Anderson and Memorial SloanKettering Cancer Centers [20]
have reported superior local control using such techniques
when compared with standard 2D methods. First, the success
of 3DCRT or IMRT depends on better delineation of the
tumor target [gross tumor volume (GTV)] by CT scan and
MRI, images of which can be co-registered, such that geo-
graphical misses are largely avoided. Secondly, there is clear
definition of the vital (mostly neural) organs in the vicinity of
the NPC such that these organs are spared a heavy radiation
dose, thus minimizing complications.
In general the clinical target volume (CTV) should include
the whole GTV and the structures in the vicinity of the tumor,
which are at substantial risk of subclinical infiltration. The
sphenoid floor, the medial aspect of the greater wings of the
sphenoid (and the foramin ovale, rotandum and lacerum), the
vomer, the posterior choanae, the pterygoid plates, the ptery-
gopalatine fossa, the posterior wall of the maxillary sinus, the
parapharyngeal spaces bilaterally [21] and the prevertebral
muscles and fascia are all at risk of tumor infiltration and
should be included in the CTV. In T3 that infiltrates the clivus
and T4 lesions, the entire clivus should be included in the
CTV. However, in T1, T2 and less extensive T3 cases sparing
the clivus, there has been no consensus on how much thick-
ness of the clivus, if any at all, should be included in the CTV.
Table 1. Staging criteria: UICC 1997 system
Nasopharynx (T)
T1 Nasopharynx
T2 Soft tissue of oropharynx and/or nasal fossa
T2a Without parapharyngeal extension
T2b With parapharyngeal extension
T3 Invades bony structure and/or paranasal sinuses
T4 Intracranial extension, involvement of cranial nerves, infratemporal fossa, hypopharynx, orbit
Regional lymph node (N)
N1 Unilateral metastasis in lymph node(s), 6 cm in greatest dimension, above supraclavicular fossa
N2 Bilateral metastasis in lymph node(s), 6 cm in greatest dimension, above supraclavicular fossa
N3 Metastasis in lymph node(s), >6 cm in dimension, in the supraclavicular fossa
Distant metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
Stage grouping
Stage 0 T in situ N0 M0
Stage I T1 N0 M0
Stage IIA T2a N0 M0
Stage IIB T2b N0 M0
T1, T2a, T2b N1 M0
Stage III T3 N0, N1 M0
T1, T2, T3 N2 M0
Stage IVA T4 N0, N1, N2 M0
Stage IVB Any T N3 M0
Stage IVC Any T Any N M1
1010
Provided that the planning target volume (PTV) is not drawn
too near to the brainstem (as described later), we recommend
that the cortex of the clivus in juxtaposition to the tumor
should be included in the CTV. In some T4 cases, the tumor
has grossly infiltrated the inferior (or even the superior) orbital
fissure and the whole bony orbit on that side should be
included in the CTV. Intracranial extension via the foramen
ovale when the tumor infiltrates laterally and superiorly
through the pterygoid muscles is frequently associated with
trigeminal nerve palsy. In such cases, the whole infratemporal
fossal contents and the greater wing of sphenoid on the side of
the lesion should be included in addition to the intracranial
component of the cancer. Occasionally the tumor may infil-
trate submucosally inferiorly to involve the oropharynx or
even the hypopharynx. In these situations, the CTV has to be
enlarged substantially in the inferior direction.
The PTV should, ideally, include the CTV with a safety
margin that adequately caters for systemic and positional
(set-up) errors (which can vary fromcenter to center). Usually,
a 5 mm safety margin should be adequate. However, the addi-
tion of safety margins in the posterosuperior direction on the
CTV is hindered by the proximity of critical neural organs
such as the brainstem, the spinal cord and the optic chiasma.
To facilitate maximal dose sparing, we recommend that the
PTV be drawn not closer to 5 mm of the critical neural organs.
In the very advanced cases where the CTV is already within
5 mm for the critical neural organs, a phasic reduction in the
PTV is required during the course of radiotherapy to avoid
severe neurological sequelae.
Although the overall local control rate of NPC (all T-stages
together) has been improved from 80% to 90% after using
3DCRT or IMRT, the major benefit is likely to be in the
advanced T-stages (T3 and T4). The early T-stages were
usually adequately irradiated with 2D-planning methods, with
little chance of geographical misses [1, 19], even though con-
ventional 2D-planning methods such as the Ho technique [1]
have been shown to adequately circumscribe, at a high radi-
ation dose, only GTV but not CTV or PTV(as described above)
[20]. Indeed, when 2D external radiotherapy was supple-
mented by intracavitary brachytherapy, long-termlocal tumor
control as high as 94% was reported for T1 and T2a [22]. For
the more advanced T-stages, local failures occurred in one-
third to two-thirds of cases after conventional 2D-planning
methods [13, 19]. These patients should benefit most from
3DCRT or IMRT in terms of improvement in long-term local
control by avoidance of geographical misses. On the other
hand, the major benefit of 3DCRT/IMRT in the early T-stages
should be reduction of severe late radiation complications
such as chronic xerostomia, which detracts significantly from
the quality of life of the long-term survivors of the disease.
Altered fractionation
In addition to improved radiotherapy techniques, use of
altered fractionation and radiation dose escalation have been
reported to improve the local control. Although a Radiation
Therapy Oncology Group (RTOG) trial [23] has proved the
superiority of both concomitant boost (accelerated hyper-
fractionated radiotherapy) and hyperfractionation over the con-
ventional daily fractionation (2 Gy per fraction, five fractions
per week) for head and neck cancers in general, the benefit for
NPC has not been addressed specifically. Subgroup analysis
for NPC was not possible in the RTOG trial due to the small
numbers of NPC cases.
Recently, we have reported a significant increase in neuro-
logical complications, especially temporal lobe encephalo-
Figure 2. Treatment results by Hos overall stage [13].
1011
pathy and cranial nerve(s) palsy, after a late-course bid
hyper-/accelerated fractionated radiotherapy in a randomized
comparison with conventional daily fractionation [24]. The
temporal lobe and some other neurological complications
arose despite keeping the interfraction time interval to 6 h.
These observations have led us to conclude that the sublethal
damage repair half-life of the central nervous tissue is likely to
be longer than previously thought [24]. Clearly, the routine
practice of a bid radiotherapy regimen together with a 2D-
planning method should be avoided unless specific measures
to avoid irradiation to neural organs are implemented [24].
This precaution is especially relevant to the advanced T-stage
NPC, the tumor target of which is often in very close proxim-
ity to major neural organs such as the optic chiasma and the
brainstem. On the other hand, improved local control by treat-
ing six fractions per week rather than five fractions per week
has been recently reported [25]. By keeping most interfraction
intervals to 24 h, the problemof inadequate sublethal damage
repair of neurons of the bid technique can be avoided.
A definite relationship between total radiation dose and the
local tumor control has been established in early T-stage NPC
when the effect of dose escalation by intracavity brachy-
therapy after 6670 Gy of external beam radiation was studied
[22]. However, brachytherapy is unable to deliver a signifi-
cant dose to bulky parapharyngeal infiltration significant skull
base involvements, or intracranial extensions, due to the geo-
metrical dose fall-off with distance from the radioactive
sources. Thus, the bulky T2b and the T3 and T4 cases benefit
little fromthis approach. However, if the dosetumor response
relationship above 6670 Gy demonstrated in early T-stage
NPC is also applicable to the advanced T-stage, dose escala-
tion above this level by means other than intraluminal brachy-
therapy should still be potentially beneficial in enhancing the
local control of T3 and T4 disease. Studies using IMRT/
3DCRT/stereotactic fractionated radiotherapy (SRT) to
boost up the total dose of the advanced T-stage NPC may
effectively and significantly improve the local control of ad-
vanced T-stage NPC, but the final goal should be an increased
therapeutic ratio when the trade off should not be an increase
in radiation toxicities, especially chronic neural toxicities.
Combined modality treatment for
locoregionally advanced disease
Although the initial remission rate is substantial with radio-
therapy alone even in locoregionally advanced, UICC stages
III and IV disease, the subsequent rates of both local and dis-
tant failures are high. Since NPC is highly chemosensitive,
efforts have been made to incorporate chemotherapy into the
primary treatment of the disease.
Following encouraging response rates to platinum-contain-
ing regimens in phase II studies in patients with metastatic
disease, the use of neoadjuvant and adjuvant chemotherapy,
combined with radiotherapy has been investigated in patients
with locoregionally advanced disease in five prospective
randomized trials (Table 2) [2630]. None of these trials
demonstrated an improvement in OS. Although the Inter-
national NPC Study Group trial showed a significant improve-
ment in progression-free survival (PFS) [28], this was only
achieved at the expense of an 8% treatment-related mortality.
Hence, outside the context of a clinical study, the use of either
neoadjuvant or adjuvant chemotherapy cannot be recom-
mended as a standard therapeutic approach.
Concurrent chemoradiotherapy
Complete remission rates of locoregionally advanced disease
to concurrent cisplatin radiotherapy in head and neck cancers,
including NPC, were high and the early relapse-free survival
Table 2. Randomized trials of neoadjuvant chemotherapy in advanced NPC
DFS, disease free survival; OS, overall survival.
Institution [reference] No. of
patients
Chemotherapy Median follow-up
(months)
Results
Prince of Wales Hospital [26] 82 Cisplatin + 5-FU 28.5 DFS no difference
2 cycles neoadjuvant OS no difference
4 cycles adjuvant
Institute Nationale Tumori [27] 229 Vincristine, cyclophosphamide,
doxorubicin
48 DFS no difference
6 cycles adjuvant OS no difference
International NPC Study Group [28] 339 Bleomycin, epirubicin, cisplatin 49 DFS improved
3 cycles neoadjuvant OS no difference
Asian Oceanian Clinical Oncology Association [29] 334 Cisplatin, epirubicin 30 DFS no difference
23 cycles neoadjuvant OS no difference
Sun Yat Sen Hospital [30] 456 Cisplatin, 5-FU, bleomycin 62 DFS improved
2-3 cycles neoadjuvant OS no difference
1012
rates were promising [31]. Cisplatin acts both as a cytotoxic
agent and as a radiation sensitizer. The optimal scheduling of
cisplatin and radiation has not yet been established, but daily
low dose, weekly intermediate dose or 3-weekly high dose
regimens have all been used.
The Head and Neck Intergroup conducted a study compar-
ing concurrent cisplatin and adjuvant cisplatin/5-fluorouracil
(5-FU) with radiotherapy against radiotherapy alone in patients
with stages III and IV NPC using the UICC1987 classification
[32]. The study was closed early after demonstrating signific-
ant OS and PFS advantage for the chemotherapy/radiotherapy
group. Since the publication of this trial in 1998, the standard
practice in North America has been concurrent chemotherapy/
radiotherapy using cisplatin 100 mg/m
2
3-weekly3, followed
by adjuvant cisplatin 80 mg/m
2
on day 1 and 5-FU 1 g/m
2
on
days 14, 3-weekly 3. However, it is noteworthy that in this
trial WHO type III histology (undifferentiated carcinoma) was
present in only 44% of patients. In endemic areas such as
southern China, the proportion of WHO type III histology will
be >90%. Whether the results of a clinical trial derived from a
heterogenous histological mix of patients can be directly
applied to WHO type III undifferentiated NPC is not certain.
Another factor that may have influenced the results of the trial
was that the radiotherapy technique was not uniform among
the participating Intergroup centers.
Furthermore, the benefit of concurrent chemotherapy
during radiotherapy and adjuvant chemotherapy after radio-
therapy cannot be separated in the Intergroup study. A ran-
domized trial of 229 patients treated in the Institute Nazionale
Tumori in Milan failed to demonstrate any survival benefit for
patients receiving four cycles of vincristine, cyclophosphamide
and doxorubicin compared with the patients receiving no
adjuvant therapy [27]. In addition, the Meta-Analysis of
Chemotherapy in Head and Neck Cancer collaborative group
meta-analysis results of head and neck cancer in general have
indicated no survival benefit of adjuvant chemotherapy [33].
These data suggest that most of the benefit of the Intergroup
0099 regimen was derived from concurrent chemotherapy/
radiotherapy.
Based on the success of concurrent chemoradiation in head
and neck cancers and the encouraging phase II data in NPC,
we embarked on a study in locoregionally advanced NPC com-
paring radiotherapy with concurrent cisplatinradiotherapy.
Patients with Hos N2 or N3 stage or N1 stage with nodal size
4 cm were eligible. Patients were randomized to receive cis-
platin 40 mg/m
2
on a weekly basis concurrently with external
radiotherapy or radiotherapy alone. A total of 350 eligible
patients were entered between April 1994 and November
1999. A preliminary PFS analysis demonstrated a trend
towards benefit for the concurrent chemotherapy/radiotherapy
arm [34]. Moreover, there was a very clear PFS benefit favor-
ing chemotherapy/radiotherapy in the subgroup of Hos T3
(UICC T3/T4) patients with a hazards ratio of 2.49 (95%
confidence interval 1.284.8). The benefit in the subgroup
of advanced T stage patients was mainly attributable to a
reduction in the rate of distant metastases. Based on the
evidence of this latter study and Intergroup 0099 Study, the
use of concurrent cisplatin/radiotherapy should become
standard therapy for endemic locoregionally advanced T and
N stage NPC patients.
Salvage of local failure after radiotherapy
Locoregional failures without distant metastases are poten-
tially curable and should be treated aggressively. In the 1970s
when the primary radiotherapy was often suboptimal in dose
and tumor target coverage, the salvage rates of locally recur-
rent NPC by re-irradiation, mainly using external beams, were
reported to be between 20 and 30% [35, 36]. However, as the
primary radiotherapy improved, resulting in more adequate
dose to the major part of the tumor, the rate of geographical
misses lessened. The tumors that fail such treatment should,
at least theoretically, be more radioresistant. Indeed, we
reported little success of re-irradiation to a high dose using
2D-planned external beams for the salvage of local relapse
[37]. Moreover, the complications of re-irradiation were many
and severe. These included severe trismus that disrupted the
patients speech and ability to eat and also radiation-induced
temporal lobe encephalopathy and cranial nerve damage caus-
ing diplopia (VI) and dysphonia (VIIIXII) and even aspira-
tion (VIIIXII ). In view of limited success but significant
morbidity, we do not recommend 2D-planned external radio-
therapy as a salvage for NPC local relapses [37].
In small (<5 cm in largest dimension) and suitably located
recurrences that spare the nasal septum and the Eustachian
cushions, over 60% long-term control was reported using
198
Au implantation [38]. This interstitial brachytherapy
delivered a very high dose to the local tumor but spared the
important organs in the vicinity because of the inverse square
law. However, it was associated with a not insignificant rate of
troublesome headache and nasopharyngeal radiation necrosis
that causes a foul smell and occasional epistaxis. In addition,
palatal wound problems and even chronic non-healing palatal
fistulas were also reported after
198
Au implantation. The great-
est drawback of this method is that it could only be applied to
a minority of cases. Even though the procedure can be per-
formed under endoscopic guidance, a split-palatal approach
had been advocated for improved visualization and hemo-
stasis [38]. Tumor infiltration of the parapharyngeal region is
also a contraindication to
198
Au implantation.
For tumors not amenable to
198
Au implantation, in the
absence of significant skull base erosion and intracranial
extension or cranial nerve(s) palsy, surgical resection of the
recurrent or persistent local tumor becomes the mainstay
salvage treatment [39, 40]. There are various approaches to
the nasopharyngectomy: transcervical, transoral and trans-
palatal, postero-lateral, transmaxillary (maxillary swing) [40]
and midface deglove [41]. There is no ideal surgical
approach that suits all cases of local relapses and there are
advantages and disadvantages associated with each approach.
1013
The surgical procedure should therefore be tailored to the
individual patient depending on the disease extent.
Treatment for distant metastases
The median survival for patients with distant metastases is
around 9 months. Several chemotherapeutic agents have been
used in the treatment of patients with locally recurrent and
metastatic NPC. Older agents including methotrexate, bleo-
mycin, 5-FU, cisplatin and carboplatin are the most active
agents, with response rates varying from 15% to 31% [42].
Newer active agents include paclitaxel and gemcitabine with
single agent response rates of 22 and 49%, respectively [43,
44]. Platinum-containing regimens have been used in phase II
trials with encouraging response rates of 3880% (Table 3)
[4550]. The response rates were clearly improved with more
intensive chemotherapy. However, the question of whether
the gain is sufficient to justify the added toxicities remains to
be answered. Hence the current standard first-line therapy for
metastatic NPC remains combination cisplatin and 5-FU.
Investigational strategies
Overexpression of the epidermal growth factor receptor
(EGFR) is a significant predictor of adverse disease-free
survival and correlates with OS in head and neck cancers.
Zheng et al. [51] reported that a strong expression of EGFR in
Chinese patients with NPC, and we have recently demon-
strated that EGFR staining correlated with poor survival in
advanced stage NPC patients [52]. C225 (cetuximab), a chi-
meric counterpart of the murine M225 antibody, is directed
against the ligand-binding site of EGFR. Encouraging pre-
liminary data in the use of C225 in combination with cisplatin
in head and neck cancers have been reported [53]. We have
recently initiated a multicenter, open-label study to evaluate
the efficacy of C225 in combination with carboplatin in
patients with recurrent or metastatic NPC who have failed one
line of platinum-based chemotherapy.
Immunotherapy
There is evidence that HLA class I-restricted cytotoxic
T-lymphocytes (CTL) play a major role in controlling EBV
infections, and if CTL-mediated control is reduced e.g. in
transplant patients receiving immunosuppressive treatment or
in HIV-infected individuals, the cell growth-transforming
ability of EBV is apparent, and life-threatening EBV-driven
lymphoproliferative diseases may occur. Furthermore, these
often regress following relaxation of immunosuppressive
treatment and recovery of the cellular immune response.
Hence there is considerable interest in the possibility of target-
ing this virus-specific immune response to treat human tumors
that carry EBV. We have shown that functional CTLs are
present in NPC tumor biopsies, and latent membrane protein
(LMP) 2-specific CTL responses can be detected in untreated
NPC patients [54]. Studies in NPC cell lines indicate that the
tumor is capable of processing endogenously expressed EBV
antigens for recognition by HLA class I-restricted CTL and
this results in lysis of the malignant cell. There is hence a
sound basis for treating NPC by boosting LMP2-specific CTL
response. We are currently investigating several strategies that
involve immunization with LMP2 peptide epitopes presented
on autologous dendritic cells in metastatic NPC.
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Table 3. Combination chemotherapy in metastatic nasopharyngeal carcinoma
a
For patients with CR.
CAPABLE, cyclophosphamide, doxorubicin, cisplatin, methotrexate and bleomycin; OR, overall response; CR, complete response; 5-FU, 5-fluoro-
uracil; N/A, not available.
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(months)
Prince of Wales Hospital [45] 42 Carboplatin + 5-FU 38 17 Mild 12
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Singapore General Hospital [47] 32 Paclitaxel + carboplatin 75 3 Moderate 12
Institute Gustav Roussy [48] 41 Cisplatin + bleomycin + 5-FU 79 19 Moderate 25
a
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